Insulin's brain impact links drugs an...(nsulin levels are depleted Gallis group ...)

In the absence of insulin, amphetamine-induced dopamine signaling was disrupted, they found. Dopamine release in the striatum was severely impaired and expression of DAT on the surface of the nerve terminal where it normally acts to inactivate dopamine was significantly reduced.

The lack of the protein on the plasma membrane prevents the amphetamine-induced increase in extracellular dopamine, and in turn, amphetamine fails to activate the dopamine pathways that stimulate reward, attention and movement, Galli noted.

The researchers then restored insulin by pulsing the hormone back into the brain of the diabetic animals and found that the system returns to normal, indicating that the lack of insulin in the striatum directly affected amphetamine action.

To connect the physiological findings to activity in the intact brain, collaborators in the VUIIS, led by Avison, developed a probe for brain DAT activity using functional magnetic resonance imaging (fMRI).

You can do molecular dissection in very well defined model systems and break the system down into its constituents, said Avison, professor of Radiology and Radiological Sciences, and professor of Pharmacology. But the question is: how does that relate to the intact brain? Whats the relevance to overall functioning in the intact system?

Working with Galli and Avison, Jason Williams, Ph.D., used fMRI to demonstrate that in normal, healthy rats with plenty of insulin, amphetamine increased neural activity in the striatum. But in diabetic animals, activity in the striatum was suppressed.

This finding is in vivo evidence that, in the intact diabetic rat, loss of insulin has compromised DAT trafficking to the plasma membrane, Avison said. These experiments show that there is likely a strong interplay between th
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